The long-term goal of this project is explore the relationship between exercise and histamine receptor activation in order to improve overall health and cardiovascular wellness. The applicant's faculty mentor has recently documented that a single bout of exercise causes sustained peripheral vasodilation within the previously active skeletal muscle and is the result of histamine receptor activation. Specifically, histamine H1 and H2 receptor activation is considered as primary cause of the sustained postexercise vasodilation. The applicant speculates that histamine receptor activation is not only responsible for postexercise vasodilation but may also play a role in improving endothelial function, arterial compliance, and stimulate vascular remodeling. However, the histamine receptor agonist has yet to be identified, but several likely pathways have been identified. Possible histamine agonists that have been identified include: 1) carnosine released or leaked from skeletal muscle 2) histamine release via mast cell degranulation and 3) de novo production of histamine. Identification of the histamine agonist will be attempted by using single leg dynamic knee extension exercise along with the placement of microdialysis fibers to remove and infuse molecules and drugs of interest in the active skeletal muscle. The specific aims for the proposed project are as follows: 1) determine the histamine H1 and H2 receptor agonist by measuring interstitial concentrations of carnosine, histamine, tryptase within previously active skeletal muscle 2) determine the role of de novo histamine production in previously active skeletal muscle. Data collected from this project will prove valuable on three fronts. First, these data will help to develop a better understanding of vascular regulation following exercise. Second, it is expected that carnosine will be identified as a significant new factor in peripheral vascular regulation. Alternatively, histamine that is usually associated with pathophysiological responses (e.g. asthma, allergies) may be established as an influential regulator of day-to-day regional blood flow. Last, data collected from this project will contribute to the understanding and development of exercise as a therapeutic modality for the treatment and prevention of cardiovascular disease. Taken together, this project will serve to enhance the health and well-being of many people through physical activity.